Mitochondrial and synaptic dysfunction is early pathological features of the Alzheimer?s disease (AD)-affected brain. Perturbed bioenergetics function, respiration failure, aberrant mitochondrial dynamics, and increased levels of reactive oxygen species (ROS) are observed in brains and peripheral tissues including platelets of subjects with AD. Amyloid-? peptide (A?) has deleterious effects on mitochondrial and synaptic function. The underlying mechanisms and strategies to repair such injury remain unclear. PTEN-induced putative kinase 1 (PINK1) is important for the maintenance of mitochondrial integrity and quality control by conferring resistance to oxidative stress and toxic insults, modulating proper mitochondrial dynamics, and by eliminating and removing damaged mitochondria via mitophagy. So far, the role of PINK1 in amyloid pathology and A?- induced mitochondrial and synaptic defects is unexplored. We hypothesize that impairment of PINK1 function contributes to chronic A? accumulation relevant to the development of amyloid pathology in AD and to mitochondrial and synaptic degeneration. The goal of this proposal is to gain new insights into the role of PINK1 in AD pathogenesis, focusing on A? accumulation/clearance, amyloid pathology, mitochondrial quality control (function, dynamics, mitochondrial clearance), and synaptic function, utilizing gene delivery of PINK1 technology, novel genetically manipulated transgenic PINK1/AD mouse models and neuronal culture with altered PINK1 levels in neurons, and human neuronal cells containing mitochondria derived from AD and normal aged-matched subjects. The outcomes of the project could present PINK1 as a potential new therapeutic target for limiting amyloid pathology and maintaining mitochondrial integrity thereby halting AD progression.

Public Health Relevance

The aim of this project is to investigate a role of PTEN-induced putative kinase 1 (PINK1) in amyloid and mitochondrial pathology, leading to synaptic degeneration relevant to the pathogenesis of Alzheimer?s disease. The outcomes of the proposed studies would also support that PINK1 might be a potential new therapeutic agent for eliminating and limiting amyloid accumulation and improving mitochondrial and synaptic function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG054320-01A1
Application #
9539108
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Opanashuk, Lisa A
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2023-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045